High quality crystals are of great value for a variety of industrial and research applications. The ability to obtain a more tightly controlled particle size distribution as well as consistent and controlled crystal habit (shape) and structure (e.g., polymorph) is highly sought after, particularly in the biotechnology and pharmaceutical industries.
Crystallization is conventionally carried out in agitated tanks to which dissolved solute or reactants are fed. Crystals produced by these crystallizers are characterized by a wide particle size distribution (PSD). The distribution of particle size fluctuates because the various mechanisms governing the PSD are inherently nonlinear and depend strongly on process conditions. Therefore, slight changes in process conditions can cause large changes in PSD. Moreover, it has been difficult to predict the PSD of the produced crystals; so it is often impossible to even anticipate these PSD changes.
The PSD resulting from an industrial crystallization process is the product of the following mechanisms: nucleation, growth, aggregation, attrition, and breakage. However, in many cases crystallization can be approximated as a two step process: nucleation followed by crystal growth. This approximation is reasonably accurate in many cases of practical interest. (A. S. Myerson, ed., 1st ed., Handbook of Industrial Crystallization. Butterworth-Heinemann Press (1993)). Nucleation is the key step, determining how many crystals are created and will participate in subsequent processes. In current crystallizers (R. C. Bennett, “Crystallizer Selection and Design”, in Handbook of Industrial Crystallization, A. S. Myerson, ed., pages 103–130, 1st ed.), nucleation and growth occur simultaneously and are controlled to a large degree by the same variables (A. D. Randolph & M. A. Larson, Theory of Particulate Processes; Analysis and Techniques of Continuous Crystallization, 2nd ed., Academic Press, San Diego (1988)). For example, supersaturation, the most important variable affecting nucleation, also controls growth rate. Consequently, one process has to be suboptimized to manage the other. The combined processes therefore underperform what should be possible if nucleation and growth are separated and individually optimized.
It is well known in the art that “seeding” (i.e., the addition of small, prepared particles that suppress homogeneous nucleation and provide surfaces upon which solute precipitates) can be used to effect some degree of control over crystal nucleation, particularly for batch processes. Many existing batch processes benefit from the use of crystal seeding. However, seeding is often poorly managed, awkward, and even dangerous. To be completely effective, the form, quality, and PSD of crystal seeds must be tightly controlled.
In practice, seeding is often accomplished by leaving the “heel” from the previous batch in the vessel. This is simply a fraction of the suspension produced in the previous batch that contains crystals that will serve as seeds for the subsequent batch. Of course, the characteristics of these seeds vary greatly depending on the attributes of the previous batch. This heel partially redissolves under the best of conditions at the start of the next batch. In practice, it may happen that the heel completely dissolves, leaving no seed whatsoever for the subsequent batch. Furthermore, leaving the heel in the vessel decreases (often substantially) the capacity of the process. Optimally, seeds are specially treated, often finely ground material of constant quality. This usually involves adding bags of dry material to a batch at precisely the right moment (when the batch becomes saturated, but not supersaturated enough to nucleate spontaneously). This is labor-intensive and hard to manage at best. In addition, special equipment may be necessary, particularly when flammable or toxic solvents are used.
Crystallizers are frequently designed with the need for a skilled operator in mind. This skilled operator must carefully perform the necessary reactant contacting, cool the requisite volume of mother liquor, and create a well-mixed environment for crystallization to serve the dual purposes of dispersing feed streams into the crystallizing suspension (magma) and of suspending the existing particles uniformly. The human element has heretofore been essential to an efficient crystallization system, particularly when seeding is used.
The above problems exist in both continuous and batch processes. It is well known in the art that in a batch cooling crystallization the total mass of solute that precipitates is determined by the difference between the initial and final values of the solute concentration in the crystallizer solution (or mother liquor) multiplied by the total solution volume. If there is only nucleation and growth, and if this solute is precipitated onto comparatively few crystals, the mean crystal size will be large. Conversely, if this amount precipitates onto a relatively large number of crystals, the relative mean crystal size will be low. Including the effects of aggregation, attrition, and breakage makes the dependencies more complicated, but often does not substantially change the overall PSD.
Although conventional continuous crystallization processes are inherently “self-seeded” because there is always a crop of crystals present after initial start-up, there is little control over crystal form. Furthermore, the concentration of crystals in the vessel is typically not controlled. Consequences include oscillatory behavior (M. B. Sherwin, R. Shinnar, & S. Katz, “Dynamic Behavior of the Well-Mixed Isothermal Crystallizer”, AlChE Journal, 13 (6):1141–1154 (1967)), and spontaneous changes in crystal form.
Typical continuous processes have a Residence Time Distribution (RTD). This means that the residence times of individual particles in the process vary about some median value. Therefore, while growing, the particles are subject to attrition and breakage for different lengths of time. This results in a distribution in particle size about a median value. Additionally, crystals grow at varying rates, known as Growth Rate Dispersion. This also contributes to the distribution of crystal size (A. D. Randolph & M. A. Larson, Theory of Particulate Processes: Analysis and Techniques of Continuous Crystallization, supra). In addition, the use of continuous crystallizers has been largely limited to large volume products because of the cost of installing a continuous process (R. C. Bennett, “Crystallizer Selection and Design”, in Handbook of Industrial Crystallization, A. S. Myerson, ed., (1993), supra.
Effective mixing in relatively large single-tank crystallizers requires relatively large agitator power input and shear rate. While having the advantage of good mixing and solids distribution, this often leads to particle attrition and breakage and uncontrolled heterogeneous nucleation from the energetic particle-particle and particle-impeller collisions (D. A. Green, “Crystallizer Mixing: Understanding and Modeling Crystallizer Mixing and Suspension Flow”, in Handbook of Industrial Crystallization, 2nd. ed., A. S. Myerson, ed., Butterworth-Heinemann Press, (2001)). Furthermore, the nucleation caused by the agitation and supersaturation is frequently not well controlled.
Ultrasound technology has been used to induce nucleation (C. J. Price, “Ultrasound—The Key to Better Crystals for the Pharmaceutical Industry”, Pharmaceutical Technology Europe, 9(10):78 (1997); L. J. McCausland, P. W. Cains, P. D. Martin, “Use the Power of Sonocrystallization for Improved Properties”, Chemical Engineering Progress, 97(7): 56–61, (2001)). When used in a conventional crystallizer, however, ultrasound often creates undesired fines. Ultrasound can only create additional nucleation. Therefore, its use (as outlined in these references) is only to provide additional nucleation in a specific location in the process. Nucleation occurring in the rest of the process is not controlled. The net effect is often to produce smaller crystals in a process, often not the desired result.
The crystals produced by the above processes may suffer from one or more of the following disadvantages: they flow poorly, cake upon shipping or storage, have a lower rate of dissolution, reaction and lower bioefficacy, and/or process poorly in subsequent steps. Moreover, many of these processes yield products with undesirable hazards, such as too many fines/dust, and/or an undesired crystal form. Significant problems are often caused when one crystal form uncontrollably converts to another. These include caking in storage, improper and (therefore unsafe) bioavailability, and process plugging (W. C. McCrone, “Polymorphism” in Physics and Chemistry of the Organic Solid State, vol. II, D. Fox et al. eds., Interscience (1965)). Finally, handling, using substandard crystals, and the undesired conversion of crystal form result in higher process costs.
It would be advantageous to develop an inexpensive process for the production of crystals by which nucleation and growth could be easily controlled and independently optimized to yield an exceptionally narrow particle size distribution of highly unified form.